The present invention relates to novel substituted hetero-cyclopentanones and cyclopentenones and derivatives thereof useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the novel compounds of the present invention act at muscarinic receptors and may be useful in treating the symptoms of cognitive decline in an elderly patient.
Disorders of cognition are generally characterized by symptoms of forgetfulness, confusion, memory loss, attentional deficits and/or, in some cases, affective disturbances. These symptoms may arise as a result of the general aging process and/or from organic brain disease, cerebrovascular disease, head injury or developmental or genetic defects.
The general decrease in cognitive function which accompanies the aging process is well accepted. The same phenomenon has been observed and documented in many lower mammals, including those routinely employed in pharmacological testing programs for screening and predicting usefulness for particular drugs in higher animals, including humans.
Although disorders of cognition often accompany the general aging process, presenile and senile primary degenerative dementia are the most common accepted causes of mental deterioration in the elderly. It has been estimated that at least ten percent of persons over 60 years of age will eventually suffer severe mental deterioration. A much larger number will experience cognitive decline of sufficient severity to impede their activities.
Many of the symptoms of cognitive disorders, especially impaired memory, are associated with decreased acetylcholine synthesis and the impairment of cholinoreceptive neurons. In the hippocampus and cerebral cortex of patients suffering from primary degenerative dementia for example, the level of enzyme choline acetyltransferase (CAT) can be reduced as much as ninety percent (see Davies, P., et al, The Lancet, 2, page 1403 (1976); Perry, E. K., et al, Journal of Neurological Sciences, 34, pages 247-265 (1977); and White, P., et al, The Lancet, 1, pages 668-670 (1977)).
Since CAT catalyzes the synthesis of acetylcholine from its precursors choline and acetyl coenzyme A, the loss of CAT reflects the loss of cholinergic or acetylcholine-releasing nerve endings in the hippocampus and cerebral cortex. There is abundant evidence that cholinergic terminals in the hippocampus are critically important for memory formation.
The cholinergic hypothesis suggest that drugs which restore acetylcholine levels or cholinergic function (i.e., cholinomimetic) are effective in correcting this deficit in neurotransmitter chemical and provide treatment of the memory impairment symptom of cerebral insufficiency. Considerable biochemical, pharmacological, and electrophysiological evidence supports the hypothesis that deficits in the cholinergic system underlie geriatric cognitive dysfunction (Peterson, C. and Gibson, G. E., Neurobiology of Aging, 4, pages 25-30 (1983)). Aged humans and nonhuman primates with decreased cognition show improved memory when they are treated, for example, with acetylcholinesterase inhibitors such as physostigmine. These agents increase the available supply of synaptic acetylcholine by inhibiting its hydrolysis.
Aminopyridines such as 3,4-diaminopyridine ameliorate age-related cognitive deficits by increasing the release of acetylcholine from presynaptic nerve terminals, thus increasing synaptic acetylcholine (see Davis, H. P., et al, Experimental Aging Research, 9, pages 211-214 (1983)).
It has been known for some time that the natural alkaloid, muscarine, has the ability to act relatively selectively at autonomic effector cells to produce qualitatively the same effect as acetylcholine. Two other agents, pilocarpine and oxotremorine, have the same principal sites of action as muscarine and acetylcholine and are thus classified as having "muscarinic" action.
A series of imidazole derivatives of the formula ##STR1## wherein R is a member selected from the group consisting of hydrogen, alkyl, aryl and aralkyl useful as antiglaucoma agents is disclosed in U.S. Pat. No. 3,470,197.
A series of imidazole derivatives of the formula ##STR2## wherein R.sub.1 is (C.sub.1-4)alkyl,
R.sub.2 and R.sub.3 independently are hydrogen or (C.sub.1-4)alkyl, PA0 R.sub.4 and R.sub.5 together are .dbd.O, .dbd.S, or .dbd.NR, wherein R is mono- or di(C.sub.1-4)alkylcarbamoyloxy, or PA0 R.sub.4 is hydrogen and PA0 R.sub.5 is hydrogen, hydroxy or --OR.sup.1, wherein R.sup.1 is (C.sub.1-4)alkyl or mono- or di(C.sub.1-4) alkylcarbamoyl useful as presynaptic muscarinic antagonists or postsynaptic muscarinic agonists is disclosed in United Kingdom Patent Application GB 2,200,910A.
Borne, R. F., et al (Journal of Medicinal Chemistry, 16, pages 245-247 (1973)) disclosed various analogs of pilocarpine. In one series the lactone ring was replaced with a cyclopentanone ring and the imidazole ring replaced with 2-, or 4-pyridyl. In the other series the lactone ring was retained and the imidazole ring was replaced with 2-, or 4-pyridyl; 4-pyrimidyl; or 2-pyrazinyl. Only the derivative in which the lactone ring was retained and the imidazole ring replaced with a 4-pyrimidyl ring possessed muscarinic activity.
However, none of the compounds disclosed in the aforementioned references suggest the combination of structural variations of the compounds of the present invention described hereinafter.
It is well known that the cholinergic hypothesis suggests that cholinomimetics, including muscarinic agents, may have potential in treating senile cognitive decline (SCD). However, the multiple development issues associated with cholinomimetics, including, for example, poor bioavailability, short duration of action, and especially parasympathetic side effects, have diminished hopes of adequate therapy with this class of agents.
The novel substituted hetero-cyclopentanones and cyclopentenones and derivatives thereof of the present invention which are related to pilocarpine may have high affinity for the muscarinic receptor and thus are expected to be useful in the treatment of the symptoms of cognitive decline in an elderly patient including Alzheimer's disease.